P o t e n t i a l F u t u re N e u ro p rot e c t i v e Therapies for N e u ro d e g e n e r a t i v e D i s o rd e r s an d S t ro k e

Rawan Tarawneh,
KEYWORDS  Parkinson disease  Alzheimer disease  Ischemic stroke  Amyotrophic lateral sclerosis  Huntington disease
MD
a,b

, James E. Galvin,

MD, MPH

a,b,c,d,

The cellular mechanisms underlying neuronal loss and neurodegeneration have been an area of interest in the last decade. Although neurodegenerative diseases such as Alzheimer disease (AD), Parkinson disease (PD), Huntington disease (HD), and amyotrophic lateral sclerosis (ALS) each have specific pathologies, they all share common mechanisms such as protein aggregation, oxidative injury, neuroinflammation, apoptosis, and mitochondrial injury that contribute to neuronal loss. Current research in these areas has focused on developing neuroprotective therapies that target each of these mechanisms. Studies from animal and cell models have greatly expanded our knowledge in this field and form the basis of clinical trials of neuroprotective therapies. Results have been variable; it is likely that no single therapy will be satisfactory, and that multiple agents working through different mechanisms or novel agents that target more than one disease mechanism may offer the best hope for a future neuroprotective therapy. This review addresses several mechanisms of disease pathogenesis in

This study was supported by grants P01 AG03991 and P50 AG05681 from the National Institute on Aging. a Alzheimer Disease Research Center, Washington University School of Medicine, 4488 Forest Park Avenue, Suite 130, St Louis, MO 63108, USA b Department of Neurology, Washington University School of Medicine, St Louis, MO 63108, USA c Department of Psychiatry, Washington University School of Medicine, St Louis, MO 63108, USA d Department of Neurobiology, Washington University School of Medicine, St Louis, MO 63108, USA * Corresponding author. Alzheimer Disease Research Center, Washington University School of Medicine, 4488 Forest Park Avenue, Suite 130, St Louis, MO 63108. E-mail address: galvinj@neuro.wustl.edu (J.E. Galvin). Clin Geriatr Med 26 (2010) 125147 doi:10.1016/j.cger.2009.12.003 geriatric.theclinics.com 0749-0690/10/$ see front matter 2010 Elsevier Inc. All rights reserved.

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neurodegenerative disease and stroke (Table 1), along with some examples of therapies targeting each of these mechanisms. Although the authors have attempted to provide a comprehensive review of the available literature, inclusion of all studies and hypotheses in this area is beyond the scope of this review.
TARGETING SPECIFIC MECHANISMS OF DISEASE PATHOGENESIS Oxidative Stress PD

The substantia nigra (SN) of PD contains high levels of reactive oxygen species (ROS) such as superoxide and perioxynitrites in conjunction with a high iron content associated with neuromelanin,1 and reduced levels of antioxidant mechanisms such as glutathione and uric acid.2,3 The mitochondrial toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) blocks the mitochondrial electron transport chain by inhibiting complex I,4 and several abnormalities in complex I and IV have been implicated in PD.5 Oxidative stress and mitochondrial dysfunction may be interrelated in a selfpropagating circle.6 Inhibition of complex I leads to excess production of the ROS that target the electron transport chain, resulting in the formation of further increased amounts of toxic radicals.6 Furthermore, the metabolism of dopamine itself creates a favorable environment for oxidative damage through intermediates such as dopamine quinone and 3,4-diydroxyphenylacetaldehyde.7 Several compounds with antioxidant properties have been studied as potential neuroprotective agents in PD. One open label study of vitamin E 3200 IU/d and vitamin C 3000 mg/d suggested that the time to levodopa (L-Dopa) was delayed by 2.5 years,8 whereas the Deprenyl and Tocopherol Anti-Oxidative Therapy of Parkinsonism (DATATOP) trial of vitamin E and deprenyl (selegiline)9 showed no benefit for vitamin E, but a modest protective effect and slowing of disease progression with deprenyl.10 In one clinical trial (TEMPO),11 patients initiated on the monoamine oxidase B (MAOB) inhibitor rasagiline at baseline were improved at 1 year compared with patients initiated on placebo and switched to rasagiline at 6 months. Results from a larger randomized trial of rasagiline monotherapy (1 or 2 mg/d) in mild PD (the ADAGIO [Attenuation of Disease Progression with Rasagiline Once-Daily] trial) were recently reported.12 Early treatment with rasagiline at a dose of 1 mg, but not 2 mg, per day provided benefits that were consistent with a possible disease-modifying effect.12 Oral coenzyme Q10 (CoQ10) 1200 mg/d was shown to slow motor deterioration, and improve activities of daily living in a 16-month randomized trial of patients with mild PD.13 Experimental animal models of PD using a toxic hydroxylated analog of dopamine 6-hydroxydopamine (6-OHDA) suggest that the detrimental effects of this

Table 1 Potential targets for novel therapies Oxidative stress Excitotoxicity Inflammation Mitochondrial dysfunction Apoptosis Protein misfolding/aggregation Neurotrophic factors Gene therapy

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compound can be blocked by the use of iron-chelating compounds, MAOB inhibitors, and antioxidants such as vitamin E.14 In a small open pilot study, the use of glutathione 600 mg intravenously (IV) twice daily in patients with PD resulted in a significant decrease in their disability scores.15
AD

Increased peroxidation of membrane lipids, DNA, RNA, and protein have all been described in AD. Oxidative stress is involved in amyloid-b (Ab) toxicity; in vitro oxidation of soluble Ab promotes its transformation into the aggregated form, creating a vicious cycle of aggregation and oxidative damage. There is in vivo evidence that amyloid aggregation can be inhibited by antioxidants, and in vitro studies suggest that the free radical scavengers, vitamin E and propyl gallate, protect neuronal cells against Ab toxicity.16 Results of clinical trials regarding the benefit of vitamin E and C on the risk of AD have been conflicting. Supplementary intake of vitamin E or C was associated with better cognitive performance in one study.17 A large 6-year follow-up study suggests that dietary intake of vitamin E is associated with a lower risk for developing AD, particularly in smokers, and irrespective of the apolipoprotein E genotype.18 On the other hand, other studies failed to show such a benefit, although vitamin E may be associated with delayed time to death, institutionalization, loss of ability to perform basic activities, and severe dementia. In addition to vitamins, numerous free radical scavengers have been used in experimental paradigms of neuronal cell death in vitro and in vivo, such as the pineal hormone melatonin, the potent lipid peroxidation inhibitors known as the 21-aminosteroids or lazaroids, mifepristone (RU486), and the female sex hormone estrogen. Early melatonin administration reduces antioxidant stress and inhibits apoptosis in animal models of AD.19 Lazaroids such as the U-74,006F or tirilazad mesylate can attenuate the increased lipid peroxidation observed in AD.20 Another series of antioxidants, the 2-methylaminochromans such as the compound U-78,517F, may be more potent and effective inhibitors of lipid peroxidation than the 21-aminosteroids.21
Stroke

Radical scavengers (such as vitamin E, sulfhydryl compounds, and nitrone spin traps), agents that promote detoxification of ROS (superoxide dismutase, catalase, or peroxidase conjugates), and agents that prevent radical generation (eg, the xanthine oxidase inhibitor allopurinol, nitric oxide synthase inhibitors, or nonsteroidal antiinflammatory agents and cyclooxygenase inhibitors) have been studied in stroke. The use of NXY-059 has been associated with clinical benefits in animal models of stroke, and was associated with a significant improvement in the modified Rankin functional scale in the Stroke-Acute Ischemic NXY Treatment-I (SAINT-I) trial.22 However, these results were not reproduced in the expanded SAINT-II trial.23,24 Ebselen and the radical scavenger edaravone (MCI-186, Radicut) were associated with clinical improvement in a small trial.25
HD

Antioxidants that have shown potential benefit in animal models of HD include thiol, the mitochondrial enzyme cofactor lipoic acid, and the combination of vitamin E and Q10.26 Treatment with Q10 was associated with reduced levels of 8-hydroxyguanosine (a marker of oxidative damage) and improved survival in R6/2 mice. There was a trend toward slowing decline in total functional capacity, although these did not reach clinical significance in a large clinical trial of Q10.27 A randomized trial of vitamin E in HD showed no benefit, although post hoc analyses suggest a possible benefit in early disease.28

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Excitotoxicity and N-Methyl-D-Aspartate Glutamate Receptors

Excessive N-methyl-D-aspartate (NMDA) receptor activation has been implicated in the pathophysiology of several neurodegenerative diseases and in stroke.
PD

Following the loss of dopamine, enhanced NMDA receptor-mediated transmission in the striatum may be part of the cascade of events leading to the generation of parkinsonian symptoms. The dopaminergic deficit results in enhanced activity of the subthalamic nucleus and increased glutaminergic output to the basal ganglia.29 Studies on dopamine denervated rats and MPTP-treated parkinsonian monkeys have provided insight into the relative abundance of different NMDA subunits in the striatum. Dopamine depletion in the 6-OHDA rat models and MPTP primate models results in relative decreases in the abundance of NMDA receptor subtype 1 (NR1) and subtype 2B (NR2B) subunits in the synaptosomal membranes, which is restored by chronic LDopa therapy.30,31 Because stimulation of NR2B-containing NMDA receptors contributes to the generation of parkinsonian symptoms,32 NR2B-selective NMDA receptor antagonists may be therapeutically beneficial for parkinsonian patients. Prior administration of NMDA receptor antagonist dizocilpine MK-801 suppresses the dopainduced increase in glutamate in 6-hydroxydopamine-lesioned rats and may therefore offer neuroprotection.33 Several NMDA antagonists have been studied in PD. Amantadine and dextromethorphan have antidyskinetic effects, and amantadine is associated with increased lifespan.34,35 On the other hand, memantine did not show any benefit in one trial.36 Selective NMDA receptor antagonists, such as ifenprodil and CP-101,606, have been developed in an attempt to avoid the side effects of nonselective blockers. Ifenprodil has antiparkinsonian actions in rat and nonhuman primates.3739 CP-101,606, reduced parkinsonian symptoms in haloperidol-treated rats and MPTP-lesioned nonhuman primates.40 Pretreatment of 6-OHDA-lesioned rats with BZAD-0, 4-trifluoromethoxy-N-(2-trifluoromethyl-benzyl)-benzamidine (BZAD-01), a novel selective inhibitor of the NMDA NR1A/2B receptor, significantly reduced the amount of dopamine cell loss and significantly improved all behavioral measures.41 When given in combination with L-Dopa-carbidopa, the NMDA antagonist remacemide has been shown to reduce parkinsonism in rodent and monkey models of PD.42 However, it failed to demonstrate a clear benefit in clinical trials.43 The usefulness of riluzole, a presynaptic inhibitor of glutamate release, as a neuroprotective agent in PD was addressed in a large multicenter randomized clinical trial, which was halted after preliminary results showed no evidence of a neuroprotective effect.44 The simultaneous blockade of AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and NMDA receptors offers substantially greater reduction in the response alterations induced by L-Dopa than inhibition of either of these receptors alone in rat and primate models of PD. Simultaneous blockade of the AMPA receptors with GYKI-47,261 and NMDA receptor with amantadine or MK-801 resulted in significant reductions in L-Dopainduced dykinesias in a primate model, whereas the wearing-off dyskinesias were completely ameliorated in rat models of PD.45
AD

Several studies have linked t and amyloid aggregation to glutamate-mediated toxicity and suggest the involvement of NMDA subunits in the pathogenesis of AD.46 In situ hybridization studies revealed lower NR1 mRNA levels in the layer III of the entorhinal cortex and dentate gyrus in AD brains.47 AD is associated with reduced levels of 2 mRNA isoform subsets of the NR1 receptor and changes in the expression of NR2A

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and NR2B in the superior temporal cortex, cingulate cortex, and hippocampus.48 Moreover, the levels of NR1 and NR2B expression decrease with disease progression. The presence of presenilin-1 in a macromolecular complex with NR1 and NR2A further supports a role for excitotoxicity in AD.49 Therapeutic intervention with high-affinity NMDA receptor antagonists, such as phencyclidine (PCP) and MK-801, is not practical because of adverse side effects. Memantine is an uncompetitive NMDA receptor antagonist and can decrease pathologic activation of NMDA receptors without affecting physiologic NMDA receptor activity.50 Memantine is associated with functional improvement in patients with AD and has been approved by the US Food and Drug Administration for the treatment of AD.50,51
Stroke

Excitotoxicity has been a widely investigated area in stroke. Ischemic neuronal injury in vitro depends on synaptic release of excitatory amino acids (EAAs) and resultant elevation of intracellular free calcium. Even transient exposure to excess excitatory amino acids is toxic to cultured neurons, and alterations in neuronal energy balance increases the vulnerability of neurons to excitotoxic damage even in the presence of physiologic concentrations of EAAs.52 Evidence that this process progresses for several hours after the ischemic insult highlights a potential role for neuroprotective strategies administered during the critical window before irreversible loss, although the exact duration of this window in humans remains unknown. The action of glutamate on NMDA receptors seems to play an important role in glutamate-mediated toxicity. Compounds that decrease glutamate levels or interfere with its binding to this receptor have been the focus of many studies.53 NMDA antagonists that have been investigated in stroke include aptiganel hydrochloride (CNS 1102, Cerestat), dextrorphan, and dextromethorphan. Their use was associated with side effects and no clear clinical benefit in clinical trials.52 Phase II trials of oral and IV forms of remacemide hydrochloride in stroke are currently under way. Magnesium ion, which electrophysiologically behaves as a noncompetitive NMDA antagonist, has demonstrated efficacy as a neuroprotective agent in focal and global models of cerebral ischemia. Two preliminary trials of IV magnesium show no evidence of adverse effects,54,55 and phase III trials are currently under way. A phase II trial of Selfotel (CGS 19755) in patients with acute stroke reported evidence of a dose-dependent toxicity.56 Selective NMDA antagonists such as ifenprodil and eliprodil (SL82.0715) have demonstrated preclinical neuroprotective efficacy, and eliprodil is currently being investigated in early phase III trials in patients with stroke. Other compounds under investigation are 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), its derivative d-CPPene, and CGS 19,755.57 Neuroprotection is evident for the presynaptic glutamate release inhibitors 619C89 and lubeluzole when administered within 6 hours of induced ischemia. Both drugs are currently in phase II trials in stroke. Partial glycine agonists, such as HA 966, L687414, and 1-aminocyclopropanecarboxylic acid (ACPC), or full antagonists, such as 7-chlorokynurenic acid and its derivatives or ACEA 1021, are effective in stroke models. Glutamate antagonists at other receptor subtypes, such as the AMPA receptors, are under evaluation.52
HD

Injections of EAAs into the striatum of rodents and primates results in neuronal death and a neurologic phenotype similar to that of HD. Intrastriatal injections of NMDA glutamate agonists, such as quinolinic acid, have been used to create animal models of HD. Animal models and human studies show evidence of decreased glutamate

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receptors, in particular the mGluR2 subtypes, downregulation of the GLT-1 glial glutamate transporter, and increased sensitization of NMDA receptors.58 The efficacy of memantine in slowing down the rate of progression was studied in a 2-year, open, and multicenter trial with promising results.59 Cannabinoid-derived drugs also offer promise in protecting neurons from glutamate mediate toxicity. Activation of neuronal CB(1) or CB(2) cannabinoid receptors attenuates excitotoxic glutamatergic neurotransmission and triggers prosurvival signaling pathways. The administration of CB(2) receptor-selective agonists reduced neuroinflammation, brain edema, striatal neuronal loss, and motor symptoms in wild-type mouse models subjected to excitotoxicity.60

Inflammation PD

There is evidence that systemic inflammation may promote microglial activation in PD, and genes implicated in PD may also influence inflammatory mediators.61 Overexpression of wild-type a-synuclein in neurons is associated with the activation of microglia, and the release of tumor necrosis factor (TNF), interleukin 1b (IL-1b), IL-6, cyclooxygenase (COX)-2, and inducible nitric oxide synthase (iNOS).62 Animal models of PD using MPTP also show evidence of recruitment of CD4 T cells to the SN.63 Minocycline, a tetracycline derivative, has been shown to reduce microglial activation and inhibit the release of potentially toxic cytokines in the striatal region of MPTP mice. Pretreatment with minocycline improved survival of dopaminergic SN neurons in animal models of PD.64 The use of nonaspirin nonsteroidal antiinflammatory agents has been associated with a 45% reduction in the risk of developing PD in one prospective study with 14 years of follow-up.65 Cytokines (particularly TNF-a) activate COX-1 and COX-2, which catalyze the conversion of arachidonic acid to prostaglandins and thromboxanes. Mixed COX-1/COX-2 inhibitors and selective COX-2 inhibitors were shown to partially protect against MPTP-induced striatal depletion in rodents.66 Further preclinical studies are needed in this area.
AD

Several inflammatory mediators may have a role in the pathogenesis of AD. In a prospective cohort study of subjects with AD, acute systemic inflammatory events were associated with an increase in the serum levels of proinflammatory cytokines67 and a 2-fold increase in the rate of cognitive decline over a 6-month period. High baseline levels of TNF-a were also found to be associated with a 4-fold increase in the rate of cognitive decline. Clinical studies suggest that nonsteroidal antiinflammatory drugs cause a delay in the onset or slow down progression of AD, through the inhibition of COX and lipooxygenases, and resultant decrease in prostaglandin synthesis and ROS formation.68 In vitro studies of neuronal cell lines have shown that glutathione depletion induces the activation of neuronal 12-lipoxygenase (12-LOX), which leads to the production of peroxides, the influx of Ca21, and ultimately to cell death.69 Exposure to glutamate is associated with induction of the enzyme COX-2, suggesting a possible role for COX inhibitors in neuroprotection.70 Compounds with antiinflammatory activity such as glucocorticoids, antimalaria drugs, and colchicines are potential areas of interest. Treatment with a moderate dose of prednisone has been shown to suppress serum levels of acute phase proteins in patients with AD.71 The neurohormone melatonin exerts inhibitory effects on b-amyloid aggregation, oxidation, and inflammation in vitro, and results in behavioral improvement in animal models.72

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The peroxisome proliferator-activated receptor (PPAR) plays an important role in regulating the expression of enzymes involved in lipid metabolism. Specific PPAR isoforms have been shown to suppress the expression of the proinflammatory cytokines IL-1, TNF, and IL-6 and decrease the activity of the transcription factors of NF-kB, AP-1, and STAT proteins. Activation of PPARa results in decreased differentiation of monocytes into activated macrophages, decreased b-amyloid-stimulated expression of IL-6 and TNF-a, and decreased expression of COX-2.73
Stroke

Several inflammatory mediators such as leukocytes, adhesion molecules, acute phase reactants, cytokines, and proteases are increased in the plasma of patients with cerebral ischemia. The early central inflammatory events include the production of ROS (eg, nitric oxide and superoxide), expression of proteolytic enzymes (matrix metalloproteinase [MMP]-9 and MMP-2), vasoactive substances (prostaglandins and cyclooxygenases), and vascular adhesion molecules (intercellular adhesion molecule 1 [ICAM-1], P-selectin, and L-selectin). Neutrophils and macrophages are considered early contributors to the production of ROS and cytokines, whereas activation of microglia and proliferation of astrocytes in the ischemic area further promote the inflammatory response in later stages.74 Inflammatory mediators (such as IL-1b, IL-6, TNF-a, IL-10, transforming growth factor beta [TGF-b] and chemokines including membrane cofactor protein 1 (MCP1), macrophage inflammatory protein 1 [MIP-1], keratinocyte-derived chemokine/chemokine [CXC motif] ligand 1/[KC/CXCL1] and fractalkine [CX3CL1]) are also found in increased levels in brain tissue in animal models of stroke. The expression of IL-1b mRNA is increased in the ischemic rat brain within hours after the induction of stroke,75 increased levels of IL-6 are seen in the plasma and cerebrospinal fluid 3 to 6 hours after experimental stroke in mice,76 and levels of proinflammatory cytokines such as IL-6, interferon-g (IFN-g), and MCP-1 become increased in the plasma within 6 hours in rodents.77 The anti-ICAM-1 antibody, enlimomab, can reduce the size of stroke when given within 1 hour of reperfusion after transient, but not permanent ischemia, in a rat stroke model. However, its use was associated with significant worsening in the modified Rankin scale and higher mortality at 90 days compared with placebo in a large clinical trial.78 Blocking neutrophil activation by a recombinant protein inhibitor of the CD11b/ CD18 receptor, UK 279,276 (Rovelizumab), within 6 hours of stroke also failed to show any benefits in one clinical trial, which was stopped prematurely. Despite promising results for IL-1 receptor antagonist in several animal studies, this drug has not been investigated in humans.79 FK506 also demonstrates benefits, particularly after transient ischemia, in animal studies and remains a potential target for studies in humans.80 Systemic administration of minocycline is protective in experimental models of focal81 or global82 cerebral ischemia. Inhibition of IL-1b converting enzyme83 or deletion of IL-1b and IL-1a results in markedly reduced ischemic damage and neuronal death in animal studies.84 Deficiency of inflammatory chemokines such as MCP-185or fractalkine86 is associated with less vulnerability to ischemic injury.
HD

Neuroinflammation is a prominent feature associated with HD and may constitute a novel target for neuroprotection. Increased expression of several key inflammatory mediators, including chemokine (c-c motif) ligand 2 (CCL2) and IL-10, has been reported in the striatum of patients with HD. There is also evidence of upregulation of IL-6, IL-8, and MMP9, in the cortex and notably the cerebellum.87 Minocycline can

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reduce calpain-mediated inflammation and caspase-dependent neurodegeneration, and was found to be neuroprotective in HD rat models. However, it cannot effectively prevent calpain-dependent neuronal death in cell culture models.88
Mitochondrial Dysfunction PD

Perhaps, the most convincing evidence for the role of mitochondrial damage in PD comes from studies of rare familial forms of PD, in which genetic mutations linked to PD result in mitochondrial impairments and increased susceptibility to oxidative stress. For example, Parkin knockouts demonstrate impaired mitochondrial activity and altered oxidative stress proteins in mouse and Drosophila models.89,90 Disruption of DJ-1, a mitochondrial protein with antioxidant chaperone activity, and mutations in PTEN-induced kinase (PINK1),91 are associated with impaired mitochondrial and proteosomal functions.92 Creatine is a precursor of the energy intermediate phosphocreatine, and transfers phosphoryl groups for adenosine triphosphate (ATP) synthesis in mitochondria. Dietary supplementation of carnitine resulted in decreased loss of dopaminergic cells in an MPTP mouse model of PD,93,94 possibly through the modulation of the Ras/ NF-kB signaling pathway. CoQ10 provides significant protection against MPTPinduced dopamine depletion.9597 A significant reduction in CoQ10 levels in mitochondria has been reported in the platelets of patients with PD, and directly correlates with a decrease in complex I activity. In one study, the oral administration of CoQ10 in patients with PD resulted in significant dose-dependent increases in plasma CoQ10 levels, and a statistically significant dose-dependent reduction in Unified Parkinson Disease Rating Scale scores compared with placebo. MitoQ contains coenzyme Q10 (CoQ10) covalently linked to the lipophilic cation triphenylphosphonium. MitoQ helps preserve mitochondrial function after glutathione depletion,98 and is currently in a phase II clinical trial for PD (http://www.parkinsons.org.nz/news/protectstudy. asp). Preliminary data also suggest that SS-31 and SS-20 (antiapoptotic mitochondrial proteins referred to as Szeto-Schiller [SS] proteins) produce complete protection against MPTP neurotoxicity.99 Others such as carnitine, b-hydroxybutyrate, and nicotinamide have been shown to protect against MPTP-induced neurodegeneration in mice.
AD

Alterations in mitochondrial size, structure, and function have been extensively reported in AD. These include deficiency in enzymes involved in oxidative metabolism (such as a-ketoglutarate dehydrogenase complex, and pyruvate dehydrogenase complex), altered calcium homeostasis, and sporadic mtDNA rearrangements. Amyloid precursor protein (APP) accumulates in mitochondria and levels of mitochondrial APP seem to directly correlate with mitochondrial dysfunction and severity of the disease. AD is also associated with abnormal distribution of mitochondria as they accumulate in the soma and are reduced in the neuronal processes of AD pyramidal neurons. Furthermore, synaptic dysfunction is one of the early and most robust correlates of AD-associated cognitive deficits, suggesting a role for Ab-induced mitochondrial dysfunction in the pathogenesis of early AD.100 Antioxidants that specifically target mitochondria are currently being studied in AD.101 A phase II clinical trial of the orally active antioxidant MitoQ is under way in AD. CoQ10 treatment has been shown to decrease brain oxidative stress, reduce b-amyloid plaque load, and improve cognitive performance in a transgenic mouse model of AD.102 Creatine administration protects against glutamate and b-amyloid

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toxicity in rat hippocampal neurons.103 Idebenone prevents b-amyloid-induced toxicity and, in combination with a-tocopherol, can improve b-amyloid-induced learning and memory deficits in rats.103,104 The administration of idebenone 90 mg three times/d orally in patients with AD was associated with statistically significant improvement of memory, attention, and behavior in a multicenter trial.105 Another randomized multicenter study trial of idebenone reported a statistically significant and dose-dependent improvement in the Alzheimers Disease Assessment Scale (ADAS) score after 6 months.106
Stroke

The release of multiple apoptogenic proteins from mitochondria has been identified in ischemic and postischemic neurons. Results from animal models strongly implicate caspase-dependent and caspase-independent apoptosis and the mitochondrial permeability transition as important contributors to tissue damage, particularly when induced by short periods of temporary focal ischemia.107 Prophylactic administration of oral creatine reduces the size of ischemic brain infarctions in mice. The antioxidant SS peptide SS-31 plays an important role in modulating ROS-induced mitochondrial permeability transition and cell death, and has been found to be protective in several in vitro and in vivo models of ischemia and reperfusion injury. Synthetic triterpenoids are analogs of oleanolic acid, which exert antioxidative effects through stimulation of the antioxidant response element Nrf2-Keap1 signaling pathway, and have been shown to be protective in a rat model of cerebral ischemia.98
HD

HD is associated with significant defects in mitochondrial respiratory enzymes, including mitochondrial succinate dehydrogenase (SDH, complex II) and aconitase. Protein aggregates interfere with mitochondrial function, mitochondrial trafficking in axons, and result in mitochondrial fragmentation and inhibition of mitochondrial fusion. SDH inhibitors, including 3-nitropropionic acid and malonate cause medium spiny neuronal loss and clinical and pathologic features reminiscent of HD in rodents and nonhuman primates.98 Results from studies on HD transgenic mice suggest that high-dose CoQ10 significantly extends survival, improves motor performance and grip strength, and reduces brain atrophy in R6/2 HD mice in a dose-dependent manner. The combination of CoQ10 and minocycline in an R6/2 mouse model of HD resulted in significantly improved behavioral measures, reduced neuropathologic deficits, extended survival, and attenuated striatal neuronal atrophy, compared with either agent alone.108 Similarly, the combination of CoQ10 and remacemide (NMDA antagonist) resulted in significantly improved motor performance and increased survival in the R6/2 and the N17182Q transgenic mouse models of HD.109 These 2 compounds were studied separately and in combination in 340 patients with HD. Administration of CoQ10 resulted in a 14% decrease in disease progression, whereas remacemide demonstrated no efficacy.27 Creatine significantly improves survival, improves motor performance, increases brain ATP levels, and delays atrophy of striatal neurons and the formation of Htt-positive aggregates in the R6/2 and N171-82Q transgenic mouse models of HD.110 Idebenone was not associated with significant improvement in a small trial in HD.111 A phase III trial of 2400 mg of CoQ10 daily has recently started in HD, and a phase II trial of CoQ10 in presymptomatic gene-positive patients with HD (PREQUEL) will begin soon.112

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PPARg co-activator 1a (PGC-1a) is a transcriptional regulator of several enzymes such as the nuclear respiratory factors 1 and 2, Tfam, and estrogen-related receptor a involved in mitochondrial biogenesis. Potential usefulness of this factor in neuroprotection has been suggested by reports of impaired expression in HD transgenic mice and patients with HD. PGC-1a induced the expression of antioxidant enzymes and its overexpression is associated with protection of neural cells from the oxidation by mitochondrial toxins.113 Sirtuins (silent information regulators) are members of the NAD1-dependent histone deacetylase family of proteins in yeast and play an important role in regulating mitochondrial function. Inhibition of sirtuins has been shown to suppress disease pathogenesis in Drosophila models of HD.114 SIRT1 activation by resveratrol has been associated with increased survival of motor neurons from transgenic ALS mice.115 In AD, SIRT1 activation by resveratrol significantly protects against microglia-dependent A-b toxicity by inhibiting NF-kB signaling and is associated with cognitive improvement in AD mouse models.115
Apoptosis

In general, antiapoptotic strategies under evaluation for neuroprotection include strategies to prevent caspase-dependent apoptosis (eg, caspase inhibitors) or strategies to prevent caspase-independent apoptosis (eg, poly(adenosine diphosphate ribose) polymerase [PARP] inhibitors).
PD

Dopaminergic cells in PD exhibit increased expression of the proapoptotic protein Bax and effector protease caspase-3 compared with controls.116 Significantly higher levels of caspase-8 activation have been demonstrated in the dopaminergic neurons of SN pars compacta of patients with PD compared with controls,117 and caspase-8 activation occurs early after exposure to cellular toxins such as 1,2,3,6-tetrahydropyridine in in vivo experimental animal models of PD. Patients with untreated PD have high peripheral levels of caspase-3 activity in lymphocytes and upregulation of antiapoptotic Bcl-2, which correlate with disease duration and severity. Treatment with LDopa and dopamine agonists is associated with lower levels of antiapoptotic Bcl-2 in the blood, and higher densities of the peripheral benzodiazepine receptor.118 CEP-1347 is an inhibitor of mixed lineage kinases, which in turn regulate the c-jun Nterminal kinase pathway (JUNK) pathway. CEP-1347 has been shown to enhance neuronal survival in cell models of PD. However, it failed to show efficacy in the early treatment of PD in one clinical study.119 Minocycline has been shown to block MPTPinduced dopamine depletion in the striatum, decreases inducible NO synthase and caspase-1 expression, and inhibits NO-induced phosphorylation of p38 mitogen-activated protein kinase. TCH 346 (N-methyl-N-propargyl-10-aminomethyl-dibenzo[b,f]oxepin [also referred to as CGP3466]) is a potent antiapoptotic drug that has been shown to prevent the loss of dopaminergic neurons in vitro, and protect against behavioral abnormalities and neurodegeneration in animal models of PD.120 This novel drug is believed to block the transcriptional upregulation of protective molecules such as Bcl-2 and superoxide dismutase.120 However, it failed to demonstrate efficacy as a neuroprotective agent in 1 randomized placebo controlled trial.121 Studies of caspase inhibitors in animal models of PD have led to mixed results. The peptidyl inhibitor carbobenzoxy-Val-Ala-Asp-fluoromethylketone (zVADfmk) can protect neurons from apoptosis induced by mitochondrial toxins. However, its therapeutic efficacy is limited by its poor penetrability into the brain.122 The more potent broad-spectrum caspase inhibitor, Q-VD-OPH, may be more promising. Specific caspase inhibitors, such as acetyl-tyrosinyl-valyl-alanyl-aspartyl-chloromethylketone

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(Ac-YVAD-cmk), have also demonstrated efficacy in several experimental paradigms of PD.123 On the other hand, other studies have found no benefit with caspase inhibitors. The treatment of 1-methyl-4-phenylpyridinium-intoxicated primary dopaminergic cultures with broad-spectrum and specific caspase-8 inhibitors triggered a switch from apoptosis to necrosis, with no overall neuroprotective benefits in one study.117 Further studies are needed in this area. Propargylamines have proven to be potent antiapoptotic agents in in vitro and in vivo studies, as these peptides can prevent mitochondrial permeabilization, cytochrome c release, caspase activation, and nuclear translocation of glyceraldehyde3-phosphate dehydrogenase.124 In fact, inhibition of apoptosis through caspase inhibition may underlie the action of the propargylamine-derived MAOB inhibitors such as rasagiline and deprenyl (selegiline).125 Moreover, rasagiline seems to induce antiapoptotic prosurvival proteins, Bcl-2, and glial cell linederived neurotrophic factor.126 In addition to its symptomatic benefits as a dopaminergic agent, selegiline has been shown to delay the need for symptomatic therapy in patients with untreated PD in the DATATOP study.9 Lazabemide is a reversible inhibitor of MAOB that is not a propargylamine. Results from a randomized double blinded study suggested a delay in the need for L-Dopa treatment and a possible neuroprotective benefit. However, studies of this compound have been discontinued by the sponsor.
AD

The activation of PARP plays a critical role in caspase-independent apoptosis. Therefore, PARP inhibitors represent one possible therapeutic strategy in AD. PARP-1 has been implicated in DNA repair and maintenance of genomic integrity. The generation of ROS causes overactivation of PARP, resulting in the depletion of NAD(1) and ATP, and consequently in necrotic cell death and organ dysfunction.127 There is evidence to suggest that apoptosis is associated with senile plaques containing Ab peptide in AD brains, and this effect may be mediated through ROS. The effect of Pycnogenol (PYC), a potent antioxidant and ROS scavenger, on Ab(2535)induced apoptosis was investigated in an animal model of AD. PYC suppressed the generation of ROS, caspase-3 activation, DNA fragmentation, PARP cleavage, and eventually protected against Ab-induced apoptosis. A significant increase in ROS formation preceded apoptotic events after the cells were exposed to Ab (2535).128
HD

Several lines of evidence point to a role for apoptosis in animal models and in postmortem tissue of HD. Caspase-3 has been shown to cleave mutant huntingtin and the activation of caspase-1 has been reported in the HD brain. The expression of expanded polyglutamine residues has been associated with apoptotic mechanisms via caspase activation and cleavage of the death substrates lamin B and inhibitor of caspase-activated DNase (ICAD).129 Bax expression in peripheral B and T lymphocytes and monocytes is increased in HD, and lymphoblasts derived from patients with HD show increased stress-induced apoptotic cell death associated with caspase-3 activation.130 Recent findings suggest a possible role for the hypoxia-inducible factor 1 (HIF-1) in HD. HIF-1 regulates the expression of several genes, including mediators of apoptosis, making it a potential target for future therapies.131 Extracellular ATP stimulates apoptosis through stimulation of P2X7 receptors, and subsequent alterations in calcium permeability, both of which have been described in HD. The in vivo administration of the P2X7-antagonist Brilliant Blue-G to HD mice prevented neuronal apoptosis and attenuated motor coordination deficits.132

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Stroke

Caspase-dependent and caspase-independent mechanisms of cell death are implicated in focal cerebral ischemia. Increased expression of Fas and of mediators of the extrinsic caspase-dependent pathway have been shown following focal ischemia. Increased expression of caspase-1, -3, -8, and -9, and of cleaved caspase-8, has been observed in the penumbra. The role for apoptosis in ischemia is further supported by reports that the inhibition of caspase-3 reduces infarct size after transient focal ischemia.133 Intranuclear MMP activity facilitates oxidative injury in neurons during early ischemia through the cleavage of PARP-1 and XRCC1, and resultant disturbance of DNA repair mechanisms. Inhibition of MMP with the broad-spectrum inhibitor BB1101 significantly attenuated ischemia-induced PARP-1 cleavage, and resultant cell death in a rat model of focal cerebral ischemia.134 The p53-dependent receptor pathway also seems to be involved in stroke-induced apoptosis. Injection of netrin-1, a ligand of the receptor uncoordinated gene 5H2 (UNC5H2), was associated with significantly reduced infarct volume at 3 days after focal ischemia in an animal model of stroke, through its inhibition of p53-mediated apoptosis.135 Estrogen has also been shown to prevent Fas-mediated apoptosis in experimental models of stroke.136
Misfolding of Protein and Protein Aggregation PD

Several animal studies and studies of familial PD have shown that the overexpression of the wild-type and the mutant forms of a-synuclein can lead to loss of dopaminergic terminals, the aggregation of a-synuclein and subsequently to motor impairment. On the other hand, a-synuclein knockouts do not display any characteristic phenotype other than minor deficits in dopamine transmission.137 Lentiviral-mediated expression of wild-type rat a-synuclein in rats resulted in the formation of aggregates but no cell loss.138 Based on these results, it is plausible that either misfolded a-synuclein , or increased amounts of normal a-synuclein, contribute to neurotoxicity in PD. Other studies have demonstrated the presence of large amounts of a-synuclein aggregates in the presynaptic region terminals. These occur in parallel with significant synaptic pathology and may, at least partially, account for the discrepancy between the number of neocortical Lewy bodies and the degree of neuronal loss or cognitive impairment.139 Much of our current understanding of possible ways to target the accumulation of asynuclein in a-synucleinopathies has been based on studies of amyloid aggregation in patients with AD. Animal and in vitro cell models suggest that the conversion of some amyloidogenic proteins from random structure to a b-sheet-rich aggregated form can be inhibited by the addition of peptides derived from the respective amyloidogenic protein.140 Previous studies on the use of peptide inhibitors in AD by the insertion of an N-methylated amino acid to provide a b-sheet-breaking peptide provided the basis for the development of methylated a-synuclein as a potential target in PD and Lewy body dementia.141 The formation of an N-methylated derivative of synuclein, by the replacement of the Gly73 with sarcosine, resulted in reduced fibril formation and markedly reduced toxicity.142,143 a-Synuclein peptide fragments that bind to full-length a-synuclein have also been studied as potential targets for inhibiting a-synuclein aggregation. Peptides derived from the N-terminal of the nonamyloidogenic component region of a-synuclein can bind to the full-length a-synuclein and block the assembly of a-synuclein into early oligomers and mature amyloidlike fibrils. Furthermore, the addition of a polyarginine-peptide delivery system has allowed the development of a cell permeable

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inhibitor of aggregation, the peptide RGGAVVTGRRRRR-amide, which inhibits ironinduced DNA damage in cells transfected with a-synuclein (A53T).143,144 A novel and potentially disease-modifying approach to a-synuclein-related disorders includes the inhibition of a-synuclein filament assembly with molecular compounds such as b-synuclein-derived small peptides.145 The fibrillization of the murine a-synuclein can be inhibited by human a-synuclein, with a possible role for at least 1 of the 6 mismatched residues between the 2 proteins, most of which were located in the C terminal region.146 Along this line, b-synuclein is a nonamyloidogenic homolog of a-synuclein and has been characterized as an inhibitor of a-synuclein aggregation either by direct interactions or indirect inhibitory effects on the accumulation of toxic a-synuclein oligomers.145 Several catecholamines, including dopamine, have been shown to exhibit inhibitory effects on a-synuclein fibrillization depending on their state of oxidation and to lead to the accumulation of a-synuclein protofibrils.147
AD

Potential inhibitors of Ab aggregation include rifampicin, 5,8-dihydroxy-3R-methyl2R-(dipropylamino)-1,2,3,4-tetrahydronaphthalene, type IV collagen, melatonin, daunomycin, glycosaminoglycans, fullerene, apomorphine derivatives, 3-indole propionic acid, nordihydroguaiaretic acid, tannic acid, 3-amino-1-propanesulfonic acid (Alzhemed or Tramiposate), salvianolic acid B, and D9-tetrahydrocannabinol among others. Several reports have shown that peptides or peptidomimetics can inhibit Ab aggregation. Peptides that incorporate N-methylated amino acids in critical positions exert such an effect. N-methylated derivatives of the aggregation-prone fragment of Ab, Ab(25-35), have been shown to prevent Ab-(25-35) aggregation and inhibit toxicity in PC12 cells. N-methylated peptides of other regions of the peptides, such as Ab(3640) may also effectively inhibit aggregation. PPI-1019 D-(His-[(mLeu)-Val-PhePhe-Leu]-NH2) is another effective N-methylated peptide inhibitor of Ab aggregation and toxicity, which uses the methylation of an amine, rather than amide, in the unacetylated N-terminus.148 The efficacy of these agents in inhibiting aggregation is sensitive to minor changes in testing conditions. However, the translation of these findings into development of disease-modifying therapies is less than straightforward. Drug development of compounds such as Alzhemed and iAb5p has been discontinued. Similarly, there has been a search for inhibitors of t aggregation. Methylene blue was the first such substance identified, followed by several anthraquinones such as daunorubicin and Adriamycin. Anthraquinone analogs can reduce the formation of t inclusions in neuroblastoma cells that overexpress a 4R human t fragment. Other inhibitors include phenothiazines, porphyrins, and polyphenols.149 Several N-phenylamine, phenylthiazolylhydrazide, and rhodanine compounds have been added to the list of the t aggregation inhibitors of interest.
HD

Expression of several molecular chaperones such as Hsp70, Hsp40, Hsp27, Hsp84, and Hsp105 has been shown to increase the solubility of polyQ proteins in Drosophila and mouse disease models. In vitro studies show that Hsp70 and Hsp40 promote the formation of soluble unstructured aggregates. The Hsp90 inhibitor geldanamycin, and its less toxic derivative 17-demethoxygeldanamycin (17-AAG), increase the expression of molecular chaperones, thereby preventing the aggregation of the polyQ protein in cell culture and animal models. Intracellular antibodies (intrabodies) that target polyQ protein and prevent its aggregation have been identified. These include the intrabody C4, which recognizes the

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N-terminal region of huntingtin protein (htt), and intrabodies MW7 and VL 12.3, which recognize regions adjacent to the polyQ stretch of htt. These antibodies can inhibit inclusion body formation in cell cultures and prevent neurodegeneration in Drosophila and yeast models of HD. Other peptides, such as polyglutamine binding peptide 1-6 (QBP1-6) and QBP1 (SNWKWWPGIFD), can interfere with the conformational changes associated with aggregation. Peptides consisting of 2 normal-length polyQ stretches connected by a spacer have been developed that can break b-pleated sheets and inhibit their aggregation, although they may be less effective than QB1.150 Orally administered molecules that can mimic the therapeutic effects of biomolecules offer another potential area for development of polyQ aggregation inhibitors. Benzothiazole derivatives, including PGL-135, offered promise in vitro and in cell culture; however, these results were not reproduced in mouse models. The green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) can potently inhibit htt aggregation in vitro and in a Drosophila model of HD. Similarly, compounds that can stabilize the native conformation may be useful in preventing aggregation. Examples of these include dimethyl sulfoxide, glycerol, trimethylamine N-oxide, and trehalose. Using a yeast model-based high-throughput screening assay, thousands of similar compounds have been identified and need to be evaluated in larger studies.150
Growth Factors and Gene Therapies

Several trophic factors have been shown to protect dopaminergic neurons when given before exposure to toxins, in in vivo and in vitro models of PD. Only a few, such as glial cell linederived neurotrophic factor (GDNF) and its relative, neurturin (NRTN, also known as NTN), have been shown to promote restoration of neurons in the aftermath of a toxic exposure, therefore making them potential therapeutic candidates for PD.151,152 However, their use has been limited by lack of effective means of delivery into the selected cell population; GDNF delivered by intracerebroventricular injection in patients had limited penetration into the putamen, and intraputaminal infusions were ineffective, probably because of limited distribution within the putamen.152 Gene therapies use a viral vector to deliver a protein of interest to specific brain regions and may be useful as a means of delivery of tropic factors.153 Preliminary results from a phase II randomized clinical trial with gene therapy for NRTN, using adeno-associated virus to deliver the trophic factor to the striatum, have recently been presented (http://www. ceregene.com/). GPI-1485 and NIL-A belong to the group of neuroimmunophilins, compounds that are derived from the immunosuppressant FK 506 (tacrolimus), but have no immunosuppressant function. Neuroimmunophilins exhibit neurotrophic effects in animal models of PD, and can easily cross the blood-brain barrier. Their exact mechanism of action is unknown, but may involve indirect stimulation of neurotrophic factor production. The results of clinical trials with these compounds have been insignificant. GPI-1046 is another neuroimmunophilin that is under development.154,155 GM-1 ganglioside, a constituent of cell membranes, has been shown to facilitate the neurotrophic action of GDNF and brain-derived neurotrophic factor (BDNF) and inhibit apoptosis in in vivo and in vitro models of PD. Phase I studies of this compound seem to be promising.125 Stem cells are pluripotential cells that offer the potential of generating unlimited numbers of optimized dopamine cells for transplantation. Stem cells can be grown and expanded in tissue culture and then induced to differentiate into dopamine neuronal phenotypes. Transplantation of these cells into the striatum has been associated with behavioral improvement in 6-OHDA rodents and MPTP monkeys.156 Results of fetal cell transplant have been inconclusive, with conflicting results

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regarding the survival of the grafts,157159 and questions remain regarding the optimization of selective dopaminergic cell transplantation.160
AD

Hippocampal neural stem cell transplantation has been shown to improve the spatial learning and memory deficits in aged transgenic mice without altering Ab or t pathologic conditions. This beneficial effect seems to be mediated through BDNF and resultant enhancement of hippocampal synaptic density.161 Estrogen modulates the expression of neurotrophic factors, such as nerve growth factor, enhances a nonamyloidogenic processing of APP, and prevents apoptosis. Observational evidence implies that use of hormone therapy at a younger age close to the time of menopause may reduce the risk of AD later in life, although initiation of estrogen therapy during late postmenopause has been associated with increased risk for dementia. Trials to address this issue are under way (Early versus Late Intervention Trial with Estrogen; Kronos Early Estrogen Prevention Study).162 Neurosteroid alloprognanolones (APa) are potent proliferative agents that can promote neurogenesis in vitro and in vivo of rodent and human neural stem cells, and are being studied in AD.
HD

Trophic factors such as Tr-kB, the receptor for BDNF, have been investigated as potential neuroprotective agents in HD. The ciliary neurotrophic factor and BDNF have a benefit in vivo in mouse models of HD. However, their use in clinical trials depends on the development of delivery methods to the brain such as the use of encapsulated cells or viral-mediated expression. Cysteamine, a candidate drug for HD, has been shown to increase BDNF levels in the brain and to induce neuroprotection in HD mouse models.150
SUMMARY

This review describes the depth and breadth of possible targets for the therapeutic intervention of diverse diseases such as PD, AD, HD, and stroke. Although each of these disorders has different causes, clinical and cognitive symptoms, disease course, duration, progression, and pathologic conditions, the underlying pathways subserving these diverse disorders share common targets. Most of these approaches will not make it to phase III clinical trials. However, in a short period of roughly 40 years from the introduction of L-Dopa for the symptomatic treatment of PD, 20 years of thrombolytic therapies for stroke, and 15 years of symptomatic treatment of AD with cholinesterase inhibitors, rapid advances in molecular biology and genetics have opened new avenues of research including the 100 or so targets discussed in this review and the hundreds more that the authors were unable to address.
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